Underlying mechanisms behind the neuroprotective effect of vanillic acid against diabetes-associated cognitive decline: An in vivo study in a rat model.

Hippocampal synaptic dysfunction, oxidative stress, neuroinflammation, and neuronal loss play critical roles in the pathophysiology of diabetes-associated cognitive decline (DACD). The study aimed to investigate the effects of vanillic acid (VA), a phenolic compound, against DACD and explore the potential underlying mechanisms. Following confirmation of diabetes, rats were treated with VA (50 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) for 8 consecutive weeks. The cognitive performance of the rats was evaluated using passive-avoidance and water-maze tasks. Long-term potentiation (LTP) was induced at hippocampal dentate gyrus (DG) synapses in response to high-frequency stimulation (HFS) applied to the perforant pathway (PP) to evaluate synaptic plasticity. Oxidative stress factors, inflammatory markers, and histological changes were evaluated in the rat hippocampus. This study showed that streptozotocin (STZ)-induced diabetes caused cognitive decline that was associated with inhibition of LTP induction, suppression of enzymatic antioxidant activities, enhanced lipid peroxidation, elevated levels of inflammatory proteins, and neuronal loss. Interestingly, chronic treatment with VA alleviated blood glucose levels, improved cognitive decline, ameliorated LTP impairment, modulated oxidative-antioxidative status, inhibited inflammatory response, and prevented neuronal loss in diabetic rats at a level comparable to insulin therapy. The results suggest that the antihyperglycemic, antioxidative, anti-inflammatory, and neuroplastic properties of VA may be the mechanisms behind its neuroprotective effect against DACD.

Parkinson's disease tremor prediction using EEG data analysis-A preliminary and feasibility study.

PURPOSE: Tremor is one of the hallmarks of Parkinson's disease (PD) that does not respond effectively to conventional medications. In this regard, as a complementary solution, methods such as deep brain stimulation have been proposed. To apply the intervention with minimal side effects, it is necessary to predict tremor initiation. The purpose of the current study was to propose a novel methodology for predicting resting tremors using analysis of EEG time-series. METHODS: A modified algorithm for tremor onset detection from accelerometer data was proposed. Furthermore, a machine learning methodology for predicting PD hand tremors from EEG time-series was proposed. The most discriminative features extracted from EEG data based on statistical analyses and post-hoc tests were used to train the classifier for distinguishing pre-tremor conditions. RESULTS: Statistical analyses with post-hoc tests showed that features such as form factor and statistical features were the most discriminative features. Furthermore, limited numbers of EEG channels (F3, F7, P4, CP2, FC6, and C4) and EEG bands (Delta and Gamma) were sufficient for an accurate tremor prediction based on EEG data. Based on the selected feature set, a KNN classifier obtained the best pre-tremor prediction performance with an accuracy of 73.67%. CONCLUSION: This feasibility study was the first attempt to show the predicting ability of EEG time-series for PD hand tremor prediction. Considering the limitations of this study, future research with longer data, and different brain dynamics are needed for clinical applications.

Effect of vitamin D on cardiac hypertrophy in D-galactose-induced aging model through cardiac mitophagy.

BACKGROUND: Cardiac apoptosis plays a key role in increased morbidity associated with aging-induced-cardiac disorder. Mitochondria play an important role in cardiac apoptosis, and dynamin-related protein 1 (Drp1), as a main mediator of mitochondrial fission, can trigger the mitophagy process to sustain the mitochondrial quality. The present study was done to determine the effect of vitamin D (VitD) treatment on cardiac hypertrophy through mitophagy regulation in aged animals induced by D-galactose (D-GAL). METHODS AND RESULTS: Male Wistar rats were randomly divided into four groups: control, D-GAL (aging group), D-GAL co-injected with VitD (D-GAL ± VitD), and D-GAL plus ethanol (D-GAL ± Ethanol). Aging was induced by an intraperitoneal (i.p.) administration of D-GAL at 150 mg/kg daily for eight weeks and also VitD (400 IU/kg) or ethanol was injected (i.p.) into aging rats. Then, the levels of cardiac mitophagy and cardiac apoptosis were determined by measuring the expression of tensin homologue (PTEN)-induced putative kinase 1 (PINK1), Drp1, Bcl2-Associated X (Bax), and B-cell lymphoma 2 (Bcl2) genes. Aging in rats was associated with a reduction in mitophagy and also an increase in apoptosis of the heart through down-regulation of Drp1, PINK1, and Bcl2 genes and also up-regulation of Bax. However, VitD improved cardiac hypertrophy through cardiac mitophagy in D-GAL-induced aging rats. CONCLUSION: VitD can inhibit cardiac hypertrophy by an increase in mitophagy and a decrease in apoptosis in the aging heart. The illustration of the suggested mechanism underlying of Vitamin D in cardiac hypertrophy induced by aging.

Association of vitamin A and its organic compounds with stroke - a systematic review and meta-analysis.

PURPOSE: The main purpose of this systematic review was to evaluate the association between the stroke (risk of stroke and the mortality due to stroke) and vitamin A, its organic compounds and its provitamins. METHOD: Major databases including PubMed, Scopus, and Web of Science were searched. Studies with human samples were included for risk assessment. The association was assessed using odds ratio (log(OR)) and a random-effect model. I2 statistic, variance (tau2) and prediction interval were used for heterogeneity assessment. The funnel plot was used for publication bias. RESULTS: Twenty-one studies including 5789 stroke patients were retrieved. Twenty studies had sufficient information for quantitative analyses. The pooled effect showed an inverse association between vitamin A and its organic compound with the risk of stroke (log(OR) = -0.46 95%CI (-0.81;-0.12)) and with the risk of mortality due to stroke (log(OR) = -0.39 95%CI (-0.74;-0.04)). However, according to subgroup analyses, the association was dependent on the compound in a way that retinol and beta-carotene were the most effective compounds. The effects of several confounding factors and the threshold levels for vitamin A and its organic compound on the effectiveness were discussed. CONCLUSION: Insufficiency of retinol and beta-carotene significantly increased the risk of stroke; however, due to heterogeneity between studies more studies are needed for evaluating clinical significance of this outcome.

Royal jelly improves learning and memory deficits in an amyloid ß-induced model of Alzheimer's disease in male rats: Involvement of oxidative stress.

Alzheimer's disease (AD) as the commonest type of dementia is associated with the cognitive function failure. Oxidative stress performs an essential role in the progression of AD. Royal jelly (RJ) is a natural product of bees with antioxidant and anti-inflammatory properties. The present research aimed to investigate the possible protective effect of RJ on learning and memory in a rat model of Aß-induced AD. Forty male adult Wistar rats were equally distributed into five groups: control, sham-operated, Aß (receiving intracerebroventricular (ICV) injection of amyloid beta (Aß1-40)), Aß + RJ 50 mg/kg, and Aß + RJ 100 mg/kg. RJ was administered daily post-surgery by oral gavage for four weeks. Behavioral learning and memory were examined using the novel object recognition (NOR) and passive avoidance learning (PAL) tests. Also, oxidative stress markers, such as malondialdehyde (MDA), total oxidant status (TOS) and total antioxidant capacity (TAC), were assessed in the hippocampus. Aß reduced step-through latency (STLr) and increased time spent in the dark compartment (TDC) in the PAL task and also decreased discrimination index in the NOR test. Administration of RJ ameliorated the Aß-related memory impairment in both NOR and PAL tasks. Aß decreased TAC and increased MDA and TOS levels in the hippocampus, whereas RJ administration reversed these Aß-induced alterations. Our results indicated that RJ has the potential to ameliorate learning and memory impairment in the Aß model of AD via attenuating oxidative stress.

The interactive effects of verapamil and CB1 cannabinoid receptor antagonist/inverse agonist, AM251 on passive avoidance learning and memory in rat.

There are reports regarding the effects of intracellular Ca2+ and synthesis and release of endocannabinoids. The secretion of endocannabinoids depends on the L-type calcium channel. The present study evaluated the involvement of the cannabinoid CB1 receptors in the effect of L-type calcium channel blocker verapamil on passive avoidance learning (PAL) in adult male rats. In this study, we examined the effects of an acute administration of the cannabinoid CB1 receptors antagonist/inverse agonist AM251 following a chronic administration of the Ca2+ channel blocker verapamil on PAL. Male Wistar rats were administered verapamil (10, 25 and 50 mg/kg) or saline intraperitoneally (i.p) daily for 13 days (n = 10/group). After this treatment period, a learning test (acquisition) was performed, and a retrieval test was performed the following day. The results indicated that chronic systemic administration of verapamil (in a dose-dependent manner) impaired memory acquisition and retrieval. Pre-training acute administration of a selective CB1 antagonist/inverse agonist, AM251 (5 mg/kg, i.p.) did not change memory acquisition and retrieval. Co-administration of the verapamil and AM251 significantly reversed verapamil-induced amnesia, suggesting a functional interaction between AM251 and verapamil. The results indicated the interactive effects of cannabinoid CB1 receptors and L-type calcium channel in passive avoidance learning and AM251 can counter the effects of verapamil on memory.

The effects of polyvinyl alcohol-coated selenium nanoparticles on memory impairment in rats.

Some mineral elements exert beneficial neuroprotection, especially in the form of nanoparticles. The aim of the present study was to evaluate the effects of selenium nanoparticles (SeNPs) and polyvinyl alcohol (PVA)-coated SeNPs (PVA-SeNPs) on Alzheimer's disease (AD) in a rat model of AD. Twenty-eight rats were randomly divided into four groups of seven rats: control, Alz, Alz + Se, and Alz + Se-PV groups. PVA-SeNPs and SeNPs were chemically synthesized and orally administrated (0.4 mg/kg) to the AD rats for one month. AD was induced by an intracerebroventricular (ICV) injection of streptozotocin (STZ). The memory function was assessed by the novel object recognition (NOR) and passive avoidance learning (PAL) tests. The expression of hippocampal brain-derived neurotrophic factor (BDNF) and stress oxidative markers (MDA and TAC), and the number of amyloid-beta (Aß) plaques were assessed using ELISA kits, biochemical methods, and Congo red staining, respectively. The results of the behavioral tests showed that the discrimination index in the NOR test increased in the Alz + PVA-SeNPs group compared to the Alz group. Memory performance in the PAL task improved in the PVA-SeNPs and SeNPs groups compared to the Alz group. The level of the BDNF in both of the Alz treatment groups (PVA-SeNPs and SeNPs) showed a significant increase compared to the Alz group. MDA levels and Aß plaques decreased in both NPs-treated Alz groups, while TAC levels decreased in all Alz groups. PVA-SeNPs were more effective than SeNPs in the improvement of the cognition deficit. The results suggest that PVA-SeNPs improve the cognition and memory deficit induced by an ICV injection of STZ through a decrease in the number of Aß plaques and malondialdehyde levels and an increase in the BDNF levels.

The effect of the mGlu8 receptor agonist, (S)-3,4-DCPG on acquisition and expression of morphine-induced conditioned place preference in male rats.

BACKGROUND: The nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP). Adult male Wistar rats were bilaterally implanted by two cannulas' in the NAc and were evaluated in a CPP paradigm. Selective mGlu8 receptor allosteric agonist (S-3,4-DCPG) was administered at doses of 0.03, 0.3, and 3 µg/0.5 µL saline per side into the NAc on both sides during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase, or before place preference test, or post-conditioning (expression) phase of morphine-induced CPP. RESULTS: The results revealed that intra-accumbal administration of S-3,4-DCPG (0.3 and 3 µg) markedly decreased the acquisition in a dose-dependent manner but had no effect on expression of morphine-induced CPP. CONCLUSIONS: The findings suggest that activation of mGlu8 receptors in the NAc dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine which may be related to the glutamate activity into the NAc and in reward pathway(s). These data suggest that mGlu8 receptor may be involved in conditioned morphine reward.

Sex differences in spatial learning and memory and hippocampal long-term potentiation at perforant pathway-dentate gyrus (PP-DG) synapses in Wistar rats.

BACKGROUND: Recent studies show that gender may have a significant impact on brain functions. However, the reports of sex effects on spatial ability and synaptic plasticity in rodents are divergent and controversial. Here spatial learning and memory was measured in male and female rats by using Morris water maze (MWM) task. Moreover, to assess sex difference in hippocampal synaptic plasticity we examined hippocampal long-term potentiation (LTP) at perforant pathway-dentate gyrus (PP-DG) synapses. RESULTS: In MWM task, male rats outperformed female rats, as they had significantly shorter swim distance and escape latency to find the hidden platform during training days. During spatial reference memory test, female rats spent less time and traveled less distance in the target zone. Male rats also had larger LTP at PP-DG synapses, which was evident in the high magnitude of population spike (PS) potentiation and the field excitatory post synaptic potentials (fEPSP) slope. CONCLUSIONS: Taken together, our results suggest that sex differences in the LTP at PP-DG synapses, possibly contribute to the observed sex difference in spatial learning and memory.

Administration of Selenium Nanoparticles Reverses Streptozotocin-Induced Neurotoxicity in the male rats.

Alzheimer's disease is the most common neurodegenerative disease associated with deposition of amyloid-beta and the increased oxidative stress. High free radical scavenging ability of selenium nanoparticles (SeNPs) has been acknowledged, so in the present study, the effects of treatment with SeNPs on Streptozotocin (STZ)-induced neurotoxicity were evaluated in the male rats. Learning and memory impairment was induced by intraventricular injection of STZ. Following induction of memory impairment, the rats received 0.4 mg/kg of SeNPs daily for one month. Memory function, antioxidant capacity, and deposition of Amyloid ß (Aß) were assessed using the shuttle box task, biochemical methods, and Congo red staining. Injection of STZ caused memory impairment, a decrease in the level of total thiol group (TTG), and an increase in the malondialdehyde (MDA) content and deposition of Aß. Administration of SeNPs reversed the neurotoxicity induced by STZ. It seems that SeNPs likely had neuroprotective effects on the animal model of Alzheimer's disease through increasing antioxidants҆ capacity.

Diabetic neovascularization defects in the retina are improved by genistein supplementation in the ovariectomized rat.

Genistein seems to have a protective and therapeutic effect on conditions associated with neovascular growth in the retina. This study investigated the angiogenesis, antioxidant, and anti-inflammatory effect of genistein on the retinas in ovariectomized diabetic rats. In this study, 40 female albino Wistar rats were divided into four groups (n = 8 per group): sham, ovariectomized group (OVX), OVX + diabetes (OVX.D), and OVX.D + genistein (OVX.D.G). OVX induced by removal of bilateral ovaries and then high-fat diet (HFD) and a low dose of streptozotocin (STZ) (1 mg/kg; intraperitoneal (IP) injection) was used for diabetes induction (OVX.D) with 8 weeks of genistein treatment (OVX.D.G). At the end of 8 weeks, the retina was removed under anesthesia. The samples were used to measure extracellular signal-regulated kinase (ERK), matrix metalloproteinase 2 (MMP-2), vascular endothelial growth factor (VEGF), and nuclear factor NF-kappa-B (NF-κB) by western blotting and inflammatory factors ELISA and oxidative stress. Measurements of glutathione (GSH) and malondialdehyde (MDA) showed that OVX and especially OVX.D significantly decreased GSH and increased MDA level in the retina, but genistein reversed these effects in OVX.D.G groups. Also, OVX and OVX.D significantly increased VEGF, MMP-2, p-ERK, NF-κB, interleukin-1beta (IL-1ß), and tumor necrosis factor alpha (TNFα) expression in the retina of OVX and OVX.D groups in comparison to the sham group (p < 0.05). However, a significant reduction of these proteins was observed in the genistein-treated group (p < 0.05). In conclusion, bilateral ovariectomy and subsequently estrogen deficiency caused the development of inflammation, neovascularization, and then retinopathy in STZ-induced diabetic ovariectomized rats. On the basis of the results, genistein administration may be a practical approach for improving symptoms and complications of ovariectomized diabetic retinopathy.

Effects of vitamin D in an animal model of Alzheimer's disease: behavioral assessment with biochemical investigation of Hippocampus and serum.

Regulatory role of vitamin D (VitD) in cognitive memory and learning has been proposed. Here, we examine the behavioral and biochemical effects of VitD in Alzheimer's disease (AD), as the most common form of dementia, in male Wistar rats. Animals (n = 48) were randomly divided into six groups: control, sham solvent, sham surgery, VitD (by intraperitoneal injection), AD (receiving intrahippocampal injection of amyloid-beta peptide, Aß), and combination of VitD and Aß. Learning and memory functions were investigated through the passive avoidance and the Morris water maze (MWM) tasks. Moreover, oxidative stress biomarkers including total antioxidant capacity (TAC), total thiol groups (TTG), lipid peroxidation (LPO), and DNA damage were assessed in hippocampus and serum. In passive avoidance task, Aß significantly impaired the step-through latency and time in dark compartment. It also increased escape latency and time spent in the target quadrant in the MWM. VitD administration attenuated the Aß-induced memory impairment in passive avoidance and MWM tests. Furthermore, VitD reduced deleterious biochemical effect of Aß by enhancing the levels of TAC and TTG in addition to decreasing LPO and DNA damage levels in both hippocampus and serum. We showed, for the first time, that VitD administration improves the impaired Aß-induced memory and that, by acting as a strong antioxidant, it can attenuate the stress oxidative biomarkers in hippocampus and serum of rats with AD. Altogether, our results provide evidence for further application of VitD in neurodegenerative disorders such as AD to enlighten the involved mechanisms.

Influence of Chronic Coenzyme Q10 Supplementation on Cognitive Function, Learning, and Memory in Healthy and Diabetic Middle-Aged Rats.

Diabetes mellitus can induce impairment in learning and memory. Cognitive and memory deficits are common in older adults and especially in those with diabetes. This is mainly because of hyperglycemia, oxidative stress, and vascular abnormalities. Coenzyme Q10 (CoQ10) can decrease oxidative stress, hyperglycemia, and inflammatory markers, and improve vascular function. Therefore, the aim of the present study was to investigate the possible effects of CoQ10 on cognitive function, learning, and memory in middle-aged healthy and diabetic rats. Adult middle-aged male Wistar rats (390-460 g, 12-13 months old) were divided into 6 experimental groups. Diabetes was induced by a single i.p. injection of streptozotocin (60 mg/kg). CoQ10 (20 or 120 mg/kg, orally by gavage) was administered for 45 days. The cognitive function and learning memory of rats were evaluated using novel object recognition (NOR) and passive avoidance tests. The discrimination index of the NOR test in the diabetic groups receiving CoQ10 (20 or 120 mg/kg) and the healthy group receiving CoQ10 (120 mg/kg) was significantly higher than that in the control group. In addition, the step through latency was significantly longer and the time spent in the dark compartment was significantly shorter in the diabetic groups receiving CoQ10 than in the control group. CoQ10 supplementation can improve learning and memory deficits induced by diabetes in older subjects. In addition, CoQ10 at higher doses can improve cognitive performance in older healthy subjects.

Effect of coenzyme Q10 supplementation on diabetes induced memory deficits in rats.

The main objective of current work was to determine the effects of low and high dose supplementation with coenzyme Q10 (CoQ10) on spatial learning and memory in rats with streptozotocin (STZ)-induced diabetes. Male Wistar rats (weighing 220 ± 10) were randomly divided into six groups: (i) Control (Con, n = 8); (ii) Control+ Low dose of CoQ10 (100 mg/kg) (CLD, n = 10); (iii) Control+ high dose of CoQ10 (600 mg/kg) (CHD, n = 10); (iv) Diabetic (D, n = 10); (v) Diabetic + Low dose of CoQ10 (100 mg/kg) (DLD, n = 10); (vi) Diabetic + high dose of CoQ10 (600 mg/kg) (DHD, n = 10). Diabetes was induced by a single intraperitoneal injection of 50 mg/kg STZ. CoQ10 was administered intragastrically by gavage once a day for 90 days. After 90 days, Morris water maze (MWM) task was used to evaluate the spatial learning and memory in rats. Diabetic animals showed a slower rate of acquisition with respect to the control animals [F (1, 51) = 92.81, P < 0.0001, two-way ANOVA]. High dose (but no low dose) supplementation with CoQ10 could attenuate deteriorative effect of diabetes on memory acquisition. Diabetic animals which received CoQ10 (600 mg/kg) show a considerable decrease in escape latency and traveled distance compared to diabetic animals (p < 0.05, two-way ANOVA,). The present study has shown that low dose supplementation with CoQ10 in diabetic rats failed to improve deficits in cognitive function but high dose supplementation with CoQ10 reversed diabetes-related declines in spatial learning.

Intracerebroventricular microinjection of kaempferol on memory retention of passive avoidance learning in rats: involvement of cholinergic mechanism(s).

Purpose of the study: Kaempferol (KM) is a flavonoid found in plant-derived foods and medicinal plants. Recently, it is well established that KM plays a protective role to develop Alzheimer's disease. The current study aimed at evaluating the effect of intracerebroventricular micro-injection of KM on memory retention of passive avoidance learning (MRPAM) and identifying the potentially related cholinergic mechanisms (ChMs) in rats. Materials and methods: In the current study, male Wistar rats randomly divided into control, vehicle and KM (10, 20 and 40 µg/rat) groups. Moreover, MRPAM was evaluated by shuttle box test. The role of ChM was studied using non-selective and selective acetylcholine antagonists (scopolamine [SCN], 4-DAMP and methoctramine [MN], respectively) as well as pirenzepine (PZ) in combination with KM. Results: The employment of KM (40 µg/rat) improved the SCN-induced memory impairment in MRPAM. Co-treatment with KM (40 µg/rat) plus 4-DAMP significantly increased the step-through latency (STL, P < 0.05; 167 ± 28 s) and decreased the total dark chamber (TDC, P < 0.05; 121 ± 31 s) compared with those of the 4-DAMP group (STL: 75 ± 13 s; TDC: 178 ± 46 s). Co-treatment with KM (40 µg/rat) plus PZ attenuated STL, and also increased TDC (P < 0.01; 220 ± 28 s) compared with those of the PZ group. Co-treatment with KM (10 and 20 µg/rat) and MN increased STL (P < 0.05), and deceased TDC compared with those of the MN group (P < 0.01). Conclusions: Totally, the results of the present study showed that cholinergic system may be involved in improving effect of KM on SCN-induced memory impairment.

Pretraining hippocampal stimulation of melatonin type 2 receptors can improve memory acquisition in rats.

BACKGROUND: Learning and memory are among the most important cognitive functions of the brain. Melatonin receptor type 2 (MT2R) is located in the hippocampus and participates in learning and memory processes. In the present study, we examined the role of hippocampal MT2R activation in the acquisition, consolidation, and retrieval of learning and memory in novel object recognition (NOR) and passive avoidance (PA) tasks. METHODS: IIK7 (0.03, 0.3, and 3 µg/µl/side), as a selective MT2R agonist, or vehicle was injected bilaterally into the dentate gyrus (DG) region of the hippocampus in rats five minutes before training, immediately after training, and five minutes before the retrieval-behavioral tasks, respectively. The discrimination index (DI) was measured in the NOR task, while step-through latency in acquisition (STLa), number of trials to acquisition (NOT), step-through latency in the retention trial (STLr), and time spent in the dark compartment (TDC) were determined in the PA task. RESULTS: The pretraining intrahippocampal injection of IIK7 at all doses significantly improved acquisition in the PA task. On the other hand, the posttraining intrahippocampal administration of IIK7 had no significant effects on consolidation. The preretrieval intrahippocampal injection of IIK7 at different doses attenuated the retrieval of memory. However, the NOR data showed that the intrahippocampal injection of IIK7 at different doses had no significant effects on the acquisition, consolidation, or retrieval in this task. DISCUSSION: Based on the findings, stimulation of MT2R could improve acquisition, whereas it had no effects on consolidation. It could impair retrieval in the PA task, while it had no effects on object recognition in rats.

Protective Effects of 5-HT1A Receptor Inhibition and 5-HT2A Receptor Stimulation Against Streptozotocin-Induced Apoptosis in the Hippocampus.

INTRODUCTION: Intracerebroventricular administration of streptozotocin (icv-STZ) induced apoptosis changes in neurons similar to Alzheimer's disease. The serotonergic system via its receptor involved in survival of neurons. The present study examined the ability of selective 5-HT1A receptor antagonist (NAD-299) and 5-HT2A receptor agonist (TCB-2) to attenuate the apoptosis caused by the icv-STZ in the rat. METHODS: The icv-STZ (3 mg/kg, 10 µL, twice) induced neuronal loss in the hippocampus of adult male rats. Animals were divided into naive control, sham-operated, STZ+saline (1 µL, icv), STZ+NAD-299 (5 µg/µL, icv), STZ+TCB-2 (5 µg/µL, icv), and STZ+NAD-299+TCB-2 (5 µg/µL of any agent, icv) groups. Following the 35 days' treatment period, neuronal apoptosis was detected using the Tunnel. Cells with morphological features of apoptotic cell were contended by microscopy. RESULTS: TCB-2 and NAD-299 administration decreased number of apoptotic neurons in the treatment group compared with the STZ group. Combined treatment of STZ rat with NAD+TCB more decreased number of apoptotic cells in compare to TCB-2 or NAD-299 treated STZ groups. CONCLUSION: Treatment with 5-HT1A receptor antagonist or 5-HT2A receptor agonist diminished apoptosis. The beneficial effect of 5HT1A receptor inhibition was potentiated with activation of 5-HT2A receptor in prevention of apoptosis in hippocampus.

5-Hydroxytryptamine receptor 6 antagonist, SB258585 exerts neuroprotection in a rat model of Streptozotocin-induced Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline. It has been suggested that 5-hydroxytryptamine receptor 6 (5-HT6R) might be involved in AD pathology. The aim of this study was to evaluate the effect of a 5-HT6R antagonist on cognition, learning, memory, and hippocampal apoptosis in an experimental rat model of AD. AD was induced by intracerebroventricular (icv) administration of streptozotocin (STZ; 3 mg/kg, 10 µL, twice). Adult, male rats were divided into the following groups: control, sham, AD (saline treatment, 1 µL icv for 30 days), and AD + SB258585 (5-HT6R antagonist, 1 µg/µL icv for 30 days). Following the treatment period, novel object recognition (NOR) and passive avoidance learning (PAL) tests were conducted to measure cognition, as well as learning and memory, respectively. TUNEL staining was used to evaluate apoptosis in the hippocampus. This study demonstrates that icv STZ injections induce apoptosis in hippocampal cells, decrease the NOR discrimination index, increase the number of trials needed to reach acquisition and the time spent in the dark compartment during PAL, as compared with sham and control groups. Subsequent administration of SB258585 in the STZ treated rats increased the NOR discrimination index, decreased the number of trials till acquisition and the time spent in the dark compartment during PAL, while decreasing neuronal apoptosis, as compared to the untreated AD group. Thus, we conclude that long-term administration of the 5-HT6R antagonist SB258585, ameliorates AD-associated cognitive and behavioral impairments through the suppression of apoptosis in the hippocampus.

Influence of hippocampal GABAB receptor inhibition on memory in rats with acute ß-amyloid toxicity.

The neurotransmitter γ-aminobutyric acid (GABA) is involved in the process of memory. It has been reported that the inhibition of GABAB receptors has beneficial effects on cognition. The aim of this study was to investigate the role of CGP35348 (a GABAB receptor antagonist) on dentate gyrus GABAB receptor inhibition and its effects on learning and memory impairments that had been induced in adult male rats by microinjection of ß-amyloid (Aß). Seventy Wistar male rats were randomly divided into seven groups: control, sham (receiving the Aß vehicle only), Aß, Aß + CGP35348 (1, 10, and 100 µg/µL), and CGP35348 alone (10 µg/µL). Memory impairment was induced by unilateral interventricular microinjection of Aß (6 µg/6 µL). Rats were cannulated bilaterally in the dentate gyrus, and then, they were treated for 20 consecutive days. Learning and memory were assessed using the novel object recognition and passive avoidance learning tests. The discrimination index and the step-through latency were significantly increased in the Aß + CGP35348 group in comparison to the Aß only group (P < 0.05 and P < 0.01, respectively). Data showed that the discrimination index was decreased in the Aß + CGP35348 group in comparison with the control group (P < 0.05) and sham group (P < 0.01). Moreover, the step-through latency was significantly decreased in the Aß + CGP35348 group in comparison to the control and sham groups (P < 0.01). Data from this study indicated that intra-hippocampal microinjection of the GABAB receptor antagonist counteracts the learning, memory, and cognitive impairments induced by Aß. It can be concluded that the GABAB receptor antagonist is a possible therapeutic agent against the progression of acute Aß toxicity-induced memory impairment.

Treadmill exercise attenuates 3,4-methylenedioxymethamphetamine-induced memory impairment through a decrease apoptosis in male rat hippocampus.

3,4-methylenedioxymethamphetamine (MDMA) leads to apoptosis in the hippocampus with consequent induction of learning and memory impairment. In this study, we have investigated the effects of treadmill exercise on memory in relation to apoptosis and oxidative stress in the hippocampi of MDMA-treated rats. Male Wistar rats received multiple intraperitoneal (IP) injections of MDMA (10 mg/kg) and exercised for one month on a treadmill (simultaneously or asynchronously with MDMA). We assessed memory function with the Morris water maze (MWM) test. Lipid peroxidation (LPO) and expression of caspase 3, Bax, and Bcl-2 were examined by the thiobarbituric acid assay (TBA) and western blot, respectively. Our results showed that asynchronous treadmill exercise could significantly improve MDMA-induced memory impairment in the MWM test. Caspase 3 expression decreased in the exercise group compared to the MDMA group. Although MDMA treatment caused an increase in the Bax/Bcl-2 ratio, the treadmill exercise reduced this ratio. Simultaneous exercise caused a reduction in lipid peroxidation in the hippocampus. This data suggests that treadmill exercise can be a useful strategy for treating memory impairment in persons with neurodegenerative disease and stimulant drug users. © 2017 Wiley Periodicals, Inc.